title: First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.
abstract: On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues.
authors.affiliation: Authors' Affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Blumenthal
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Scher
authors.forename: Patricia
authors.initials: P
authors.lastname: Cortazar
authors.forename: Somesh
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Shenghui
authors.initials: S
authors.lastname: Tang
authors.forename: Pengfei
authors.initials: P
authors.lastname: Song
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Kimberly
authors.initials: K
authors.lastname: Ringgold
authors.forename: Anne M
authors.initials: AM
authors.lastname: Pilaro
authors.forename: Amy
authors.initials: A
authors.lastname: Tilley
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: King
authors.forename: Laurie
authors.initials: L
authors.lastname: Graham
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Rellahan
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Weinberg
authors.forename: Bo
authors.initials: B
authors.lastname: Chi
authors.forename: Colleen
authors.initials: C
authors.lastname: Thomas
authors.forename: Patricia
authors.initials: P
authors.lastname: Hughes
authors.forename: Amna
authors.initials: A
authors.lastname: Ibrahim
authors.forename: Robert
authors.initials: R
authors.lastname: Justice
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D017277:Drug Approval; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab